The sustained delivery of pharmaceutical agents with low systemic toxicity is desirable for the treatment of systemic diseases including, but not limited, to malignancy and certain infections. Medication can be administered in a variety of ways including orally, aerosolized inhaled, subcutaneously, intramuscularly, intraperitoneally, transcutaneously, and intravenously. Drug delivery refers to approaches, formulations, technologies, and systems for transporting a pharmaceutical compound in the body as needed to safely achieve a desired therapeutic effect. Conventional drug delivery may involve site-targeting within the body or facilitating systemic pharmacokinetics. In either case, conventional drug delivery is typically concerned with both quantity and duration of drug presence.
Unfortunately, systemic administration of drugs can result in unwanted toxicity. Toxicity resulting from the systemic administration of many drugs is often related to total systemic drug exposure. Intravenous and systemic drug therapy most commonly fails due to one or more of poor drug solubility, localized tissue damage upon drug extravasation, short in-vivo stability of drug, unfavorable drug pharmacokinetics, poor biodistribution, and lack of selectivity for disease target. Variability in how individual patients absorb the drug into plasma and clear the drug from systemic circulation may account for a significant component of patient-to-patient differences in toxicity and differences in toxicity for an individual patient from day-to-day. Pharmacokinetic variability may result from day-to-day changes in an individual patient's ability to metabolize or excrete drug, or from between-patient differences in drug metabolism or excretion. Generally, drugs administered intravenously (i.e., through IV) have a relatively limited half-life due to clearance from plasma through protein binding and excretion. The concentration of drug needed to be administered systemically to be effective is typically constrained by the maximum tolerated dose or rate of administration due to systemic toxic effects. This limitation reduces the possibility of delivering a sustained and efficacious drug level due to toxicity. As a result, targeted tissues do not sustain an even level of drug for more than short times. This can lead to undertreatment of target tissue and results in the opportunity to select for the emergence of chemoresistant disease. Localized drug delivery at the site of disease is preferred to reduce off-target systemic toxicity, but has been challenging to achieve.
Many of the pharmacological properties of conventional (“free”) drugs can be improved through the use of drug delivery systems providing sustained release of biological and chemotherapeutic agents. Methods of regulated, slow, and localized drug release have considerable pharmacodynamic advantages for increasing the drug's efficacy. Drug delivery can be advanced by controlling the diffusion of drugs through polymeric matrices and/or the degradation of these polymers.
Sustained, localized drug release enables superior patient compliance and patient outcomes by increasing the therapeutic index of drugs. Sustained and slow drug release is usually achieved either by incorporation of a therapeutic drug into an implantable reservoir or by implantation of biodegradable or non-biodegradable materials containing the desired drug. The drug can be actively expelled at a defined rate with a pump. Alternatively, drug can be released passively from the implant by diffusion, erosion, or a combination of the two.
The development of biodegradable chemotherapeutic drug delivery implants is useful for the treatment of localized disease (e.g., malignancy or antimicrobial compounds for treating postsurgical infections or focal infections in immuno-compromised patients, etc.) Efficacies of slow drug release systems are usually determined by measurement of concentrations of the implanted drug in plasma or by assessment of the underlying disease treated (e.g., improving infection or decrease in the size of cancer, prevention of recurrence, etc.). For example, cancer chemotherapy delivery implants placed on a surgical margin would reduce the risk of localized recurrence. Chest wall tuberculosis requires surgical resection in most cases and complete surgical resection may be needed to keep the recurrence rate low. For patients with tuberculosis who undergo surgical resection, localized antimicrobial delivery at the surgical margin would assist in patient treatment compliance, increase treatment efficacy, and reduce the development of drug resistant organisms, as is common in aspergillosis and tuberculosis patients.
In the case of operable lung cancer, when a patient is deemed physiologically healthy, surgical resection is the treatment of choice. The operation for treating lung cancer is typically a pneumonectomy, or lobectomy, anatomic resection along with its vascular supply, and lymphatic drainage and wedge resection. Instead of a pneumonectomy or lobectomy procedure, the physician may choose to perform a wedge resection. Wedge resectioning involves the removal of an irregular triangle-shaped slice of tissue mass including the tumor or lesion, followed by surgical suturing via staple line or the edges of the resection margin are then approximated with a running locked suture to prevent air and blood leaks. In general, repair of the wedge resection is by way of the staple/resection line allowing the underlying organ to retain its shape without distortion. Typically, a wedge resection leaves just a single stitch line or staple line. Despite the advantages concerning the operation procedure, wedge resections have not been considered an acceptable oncological resection method for cancer in patients who are fit physiologically to undergo lobectomies. What makes a wedge resection undesirable in cancer patients is the 19% rate of localized recurrence of cancer at the resection margin.
One method of localized treatment of resection margins used to prevent recurrence is brachytherapy. Brachytherapy involves application of a vicryl patch/mesh, into which brachytherapy seeds are sewn. The biodegradable mesh with radioactive seeds is then affixed to the lung tissue covering the resected area. Such a brachytherapy mesh is introduced though thorachotomy or minimally invasively through intercostal access with video assisted thorascopic surgery (VATS) and attached covering a resection staple line. A study found that the wedge and brachytherapy resulted in 1% local recurrence (LR), while wedge alone resulted in a 19% LR (see d'Amato et al., “Intraoperative Brachytherapy Following Thoracoscopic Wedge Resection of Stage 1 Lung Cancer”, Chest Off. Pub. Of the Am. Coll. Of Chest Phys., 114(4):1112-5 Oct. 1998). However, despite the finding of positive results regarding the brachytherapy and wedge resection treatment combinations, the procedure has associated disadvantages. First, it is very operator dependent. Second, reproducibility is tedious, especially in video-assisted cases adding an hour or more to the already complicated procedure in physiologically compromised patients. Third, medical staff are irradiated during the surgical preparation and procedure. These disadvantages have prevented the wide adoption of brachytherapy.
In many surgical procedures, including those involved in open and endoscopic surgery, it is often necessary to fasten, staple, suture, glue, clip or clamp tissue together. Clinicians have been clamoring for a method of localized administration of drugs to various resection margins. The difficulty in precise placement of drug at the site of disease and lack of sustained therapeutic concentrations of drug at the site of disease delivered by iv has hampered the ability to deliver localized therapy used to treat malignant and non-malignant diseases. Various exemplary embodiments of the present invention simply and uniquely solve these two presently intractable problems in novel ways.